Risk of post-pregnancy hypertension in women with a history of hypertensive disorders of pregnancy: nationwide cohort studyBMJ 2017; 358 doi: https://doi.org/10.1136/bmj.j3078 (Published 12 July 2017) Cite this as: BMJ 2017;358:j3078
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The uniqueness of female patients with cancer patients: are we aware of female specific risk factors in cardio-oncology?
We really appreciated your paper (1) , the importance of hypertensive disorders of pregnancy (HDP): preeclampsia (PE) and pregnancy-related hypertension (PRH) in increasing cardiovascular disease (CVD) risk in women, outlined in 2011 Guidelines for CVD prevention (2), has been stressed in 2016 Guidelines on CVD prevention (3). Unfortunately, the awareness of the problem is still scarce and even though we are debunking the myth that CVD is a man’s disease and have a greater knowledge of “sex and gender” differences in CVD, the “uniqueness” of female gender in cancer has not been fully addressed, yet.
The topic is challenging when female patients with a history of HDP need cancer treatment. As a cardiooncologist, I was particularly intrigued, some years ago, by the early occurrence of Sunitinib-induced left ventricular dysfunction in a patient with metastatic renal cancer and a history of PE (4). It seemed clear that PE had a relevant role in determining the cardiotoxicity of the antiangiogenic (AA)-agent. In PE the impaired remodeling of the placental spiral arteries to accommodate the increased blood flow demand causes placental production of soluble factors such as the fms-like tyrosine kinase 1 (sFlt-1). sFlt-1 is upregulated in the circulation of PE women, it binds to Vascular Endothelial Growth Factor (VEGF) and Placental Growth Factor (PlGF) mimicking an AA-effect that leads to hypertension, proteinuria and edema (5).
Activation of the endothelin system is now emerging as an important pathway leading to PE(6); other circulating markers for endothelial activation (ICAM-1, VCAM-1) are upregulated, too, due to activin A elevation. But HDP, especially PE, do not end with the delivery of the placenta (7), leaving the woman “at risk forever”; she is likely to become hypertensive (in your study, rates of post pregnancy hypertension in the year after a woman’s latest delivery was 12-fold to 25-fold higher in women with a HDP) and she will be vulnerable to many stressors. With this idea of “liability” of female cancer patients with a history of PE, we performed, in these patients, in our institution, a stress/rest myocardial perfusion test to evaluate myocardial perfusion imaging (MPI) and coronary flow reserve CFR) (8). We found MPI defects and reduction of CFR even before cancer therapy and enhanced vasculotoxicity with increased MPI defects and greater reduction in CFR early after Radiotherapy (RT) for left breast cancer (LBC). Even with few preliminary data and a short follow-up period we think that women with a HDP have a “vulnerable” endothelium. With AA-drugs, the enhanced cardiotoxicity can be explained by the impressive similarities between AA-side effects and complications of pregnancy, both including hypertension, proteinuria, thrombosis and cardiomyopathy with a unifying central role for VEGF (9) and a crucial role of endothelin in both conditions (6).
But the AA-like “status” of these women is likely to interact with all kinds of vasculotoxic therapies. “Vasculotoxicity” is a new entity of cardiotoxicity, ranging from endothelial cell damage leading to hypertension and accelerated atherosclerosis, to acute vascular events such as myocardial infarction or stroke. We all know the impact of thoracic RT on coronary endothelium especially in LBC patients (10), the manifestations of coronary artery disease with Fluropyrimidines (11) and Platinum compounds and more recently we have been challenged by AA-induced hypertension (12). But there are emerging issues, too: unexpected “vasculotoxicities” of new targeted therapies on peripheral arteries(13), unpredicted “vascular” components of trastuzumab cardiotoxicity or “vascular phenotypes” of anthracycline cardiotoxiciy mediated by their effects on the vascular system (reduction of coronary branching, capillary density and expression of VEGF) (14). In accordance with the different types of myocardiotoxicity: the irrevessible type I (doxorubicin-like) and the reversible type II (trastuzumab-like)(15), two different types of chemotherapy-related vasculotoxicity have been recently proposed; the irreversible one (type I) and the “reversible “ one (type II) (16) and they are likely to be amplified in patients with a damaged endothelium that failed the stress of pregnancy.
We should therefore re-think cardiooncology also as a gynecardiooncology issue; in female cancer patients a tailored history has to include gynecologic history: complications of pregnancy, age at menopause. Premature menopause is a crucial risk factor, but HDP should be considered “warning” signs of an impaired vascular system. Not only CVD but also cancer can be a different disease in males and females and we must increase the awareness of the “uniqueness” of female patients with cancer. In this scenario cardiooncologists have the most difficult job, in female patients with cancer and a history of HDP they should be able to predict the likelihood of cardiotoxicity, especially in patients who are going to be long term survivors (e.g. early breast cancer); in these women a stress test at baseline may help to evaluate the impairment of cardiovascular reserve in order to start more aggressive treatment of all risk factors and to plan more careful monitoring.
Clinical cardiologists should be committed, too, they should include gynecologic history in the evaluation of female patients, and gynecologists should be committed even earlier to start preventive measures in the post partum period, with a strict follow up. A multidisciplinary and translational approach is needed: molecular mechanisms of cardiotoxicity of targeted cancer therapy are beginning to be elucidated, they can unravel functional roles played by kinase in key pathways of myocardiocyte survival and of endothelial cell function; the similarities between AA-side effects and PE can also shed light on molecular mechanisms of PE, thus leading to more “tailored” treatments for both PE and cancer.
There are some appealing therapeutic options: targeting the activin signaling, blocking the endothelin system, reducing sFlt-1 and soluble endoglin secretion with metformin, using the phosphodiesterase inhibitor sildenafil with its effect on NO. The idea of Gynecardiooncology is very challenging and may become, in the near future, an extremely valuable “gender based” tool in precision medicine. In the mean time, awareness of female specific risk factors especially HDP should increase in the clinical setting, with the aim of reducing the burden of CVD, the number one killer in females.
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Competing interests: No competing interests